title: Formation of assemblies on cell membranes by secreted proteins: molecular studies of free λ light chain aggregates found on the surface of myeloma cells.
abstract: We have described the presence of cell-membrane-associated κFLCs (free immunoglobulin light chains) on the surface of myeloma cells. Notably, the anti-κFLC mAb (monoclonal antibody) MDX-1097 is being assessed in clinical trials as a therapy for κ light chain isotype multiple myeloma. Despite the clinical potential of anti-FLC mAbs, there have been limited studies on characterizing membrane-associated FLCs at a molecular level. Furthermore, it is not known whether λFLCs can associate with cell membranes of myeloma cells. In the present paper, we describe the presence of λFLCs on the surface of myeloma cells. We found that cell-surface-associated λFLCs are bound directly to the membrane and in an aggregated form. Subsequently, membrane interaction studies revealed that λFLCs interact with saturated zwitterionic lipids such as phosphatidylcholine and phosphatidylethanolamine, and using automated docking, we characterize a potential recognition site for these lipids. Atomic force microscopy confirmed that membrane-associated λFLCs are aggregated. Given the present findings, we propose a model whereby individual FLCs show modest affinity for zwitterionic lipids, with aggregation stabilizing the interaction due to multivalency. Notably, this is the first study to image FLCs bound to phospholipids and provides important insights into the possible mechanisms of membrane association by this unique myeloma surface antigen.
authors.affiliation: School of Medical and Molecular Biosciences, University of Technology Sydney, Ultimo, NSW 2007, Australia. andrew.hutchinson@uts.edu.au
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hutchinson
authors.forename: Ansha
authors.initials: A
authors.lastname: Malik
authors.forename: Mark B
authors.initials: MB
authors.lastname: Berkahn
authors.forename: Mark
authors.initials: M
authors.lastname: Agostino
authors.forename: Joyce
authors.initials: J
authors.lastname: To
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Tacchi
authors.forename: Steven P
authors.initials: SP
authors.lastname: Djordjevic
authors.forename: Lynne
authors.initials: L
authors.lastname: Turnbull
authors.forename: Cynthia B
authors.initials: CB
authors.lastname: Whitchurch
authors.forename: Allen B
authors.initials: AB
authors.lastname: Edmundson
authors.forename: Darren R
authors.initials: DR
authors.lastname: Jones
authors.forename: Robert L
authors.initials: RL
authors.lastname: Raison
authors.forename: Paul A
authors.initials: PA
authors.lastname: Ramsland
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000378:metabolism*; D018625:Microscopy, Atomic Force; D062105:Molecular Docking Simulation; D009101:Multiple Myeloma; D010713:Phosphatidylcholines / Q000378:metabolism; D011485:Protein Binding
chemical_list: D007147:Immunoglobulin Light Chains; D010713:Phosphatidylcholines